The Specific Aims of the proposal are: 1) To dissect the role of PI3-K in the regulation of signalling protein (MEK and MAPK) activation in hematopoietic cells using constitutively active and dominant negative PI3-K mutants. 2) To biochemically and genetically identify the novel MEK activator in the wortmannin-sensitive, IL-3-inducible MEK activation pathway. 3) To determine the roles of MEK and MAPK and upstream regulators in hematopoietic cell proliferation and survival using transient and long-term proliferation assays. These studies are designed to characterize a discreet wortmannin-sensitive MAPK activation pathway that based on preliminary data may have cell type-specific components. Once identified these components will provide novel signal-transducing targets for pharmacological intervention to block cytokine-dependent proliferation of leukemic and normal myeloid lineage cells.